Method of providing aripiprazole to patients having impaired cyp2d6 or cyp3a4 enzyme function

ABSTRACT

The disclosed embodiments relate to methods of initiating aripiprazole treatment in a patient who is a CYP2D6 poor metabolizer or a CYP3A4 poor metabolizer, or both.

BACKGROUND

Aripiprazole can be administered to treat schizophrenia, bipolar mania(e.g., bipolar I disorder), depression, irritability associated withautistic disorder, agitation associated with schizophrenia or bipolar Idisorder, and other psychological disorders. For some patients, once aday administration of a dosage form that systemically releasesaripiprazole can be problematic, because patients with these disordersmay be unwilling or unable to take medication every day. Anintramuscular depot formulation that systemically releases aripiprazoleover a long period of time can be helpful. However, once theintramuscular depot is administered, adjusting the dosage to account forvariations in the patient population is difficult.

SUMMARY OF THE INVENTION

In various embodiments, the present invention is directed to methods ofsystemically delivering aripiprazole to a patient, particularly patientshaving impaired CYP2D6 or CYP3A4 enzyme function. In one embodiment, thepresent invention comprises administering intramuscularly to a patient,a starting dose of a long-acting drug-containing suspension whichsystemically releases therapeutic plasma levels of aripiprazole over aperiod of about one month to a patient, wherein said patient hasimpaired CYP2D6 or CYP3A4 enzyme function. Patients with impaired CYP2D6or CYP3A4 enzyme function include, for example a patient who is a CYP2D6or CYP3A4 poor metabolizer, a patient concomitantly administered astrong CYP3A4 and/or CYP2D6 inhibitor, or a patient who is a CYP2D6 orCYP3A4 poor metabolizer and is concomitantly administered a strongCYP3A4 and/or CYP2D6 inhibitor. In various embodiments, the dose oflong-acting drug-containing suspension providing therapeutic plasmalevels of aripiprazole administered to such patient with impaired CYP2D6or CYP3A4 enzyme function is adjusted such that the starting doseprovides no more than about 75%, about 75%, no more than about 50%,about 66% to about 75%, or about 50%, of the amount of aripiprazolecompared to an initial dose recommended for a patient with normal CYP2D6and CYP3A4 enzyme function (i.e., who is neither a CYP2D6 poormetabolizer nor a CYP3A4 poor metabolizer and is not concomitantlyadministered a CYP2D6 or CYP3A4 inhibitor or inducer, or other agentswhich modify CYP2D6 or CYP3A4 function). In other embodiments, thepatient with impaired CYP2D6 or CYP3A4 enzyme function is a CYP2D6 orCYP3A4 poor metabolizer. In still other embodiments the patient withimpaired CYP2D6 or CYP3A4 enzyme function is a CYP2D6 poor metabolizer.In still other embodiments the patient with impaired CYP2D6 or CYP3A4function is a CYP3A4 poor metabolizer. In some embodiments, the patientwith impaired CYP2D6 or CYP3A4 enzyme function is an extensivemetabolizer who has been concomitantly administered a strong CYP2D6inhibitor or a strong CYP3A4 inhibitor. In some embodiments, the patientwith impaired CYP2D6 or CYP3A4 enzyme function is an extensivemetabolizer who has been concomitantly administered both a strong CYP2D6inhibitor and a strong CYP3A4 inhibitor. In yet other embodiments, thepatient is schizophrenic and/or aripiprazole naïve. In particularembodiments, the starting dose of the present method systemicallyreleases no more than about 160 mg, no more than about 200 mg, or nomore than about 300 mg of aripiprazole per dose. In some embodiments,the patient is coadministered an oral antipsychotic for at least thefirst 14 days after administration of said starting dose of thelong-acting drug containing suspension. In some embodiments thelong-acting drug-containing suspension comprises aripiprazole or aprodrug thereof. In some embodiments, the long-acting, drug containingsuspension comprises s(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is the chemical structure of aripiprazole; and

FIG. 2 is a the chemical structure of the aripiprazole prodrug(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl dodecanoate.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the disclosure, singular forms such as “a,” “an,” and “the”are often used for convenience. However, it should be understood thatthe singular forms are intended to include the plural, except whencontext or an explicit statement indicates that the singular alone isintended. It should also be understood that all patents, publications,journal articles, and the like that are mentioned in this Applicationare incorporated by reference in their entirety and for all purposes.

“Aripiprazole” includes the compound7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy-3,4-dihydroquinolin-2(1H)-one,the structure of which is shown in FIG. 1, as well as pharmaceuticallyacceptable salts thereof.

“Initiating aripiprazole treatment” includes starting a patient on aparticular dosing or medication regime involving systemically deliveringaripiprazole to a patient. At the time of initiating aripiprazoletreatment, the patient may have been previously treated with anotherdrug, or by aripiprazole under a different dosing regime.

An “aripiprazole prodrug” or “prodrug of aripiprazole” is a moleculethat releases aripiprazole by forming aripiprazole or its activemetabolite (i.e., dehydroaripiprazole) in situ in the body of a patient.

A “patient” is a living organism, typically a human.

“Long-acting” refers to drug compositions that provide or releaseclinically effective amounts of one or more drugs, particularlyaripiprazole, over an extended period of time, typically over a timeperiod of about one week to about one month.

A formulation which “releases” aripiprazole or an“aripiprazole-releasing” formulation refers to a formulation whichcontains aripiprazole itself, or a formulation which contains a prodrug(e.g.,(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate) or other form of aripiprazole which forms aripiprazole insitu in the body of a patient.

When the amount of a component of a composition or formulation isexpressed as a percentage, the percentage is a weight/weight percentagebased on the total weight of the composition or formulation unlessotherwise specified.

All terms not specifically defined herein should be given the ordinarymeaning that a person of skill in the art at the time of the inventionwould ascribe to them.

Atypical antipsychotic drugs such as aripiprazole are used to treatchronic conditions such as schizophrenia, and therefore a typicalpatient will be dosed with aripiprazole over long periods of time (oftenlifelong). It is important that the aripiprazole plasma levels in apatient be maintained within an appropriate therapeutic range in orderto maximize the clinical benefit (i.e., control of schizophrenicsymptoms, preventing mania, stabilizing mood, etc.), while minimizingpotentially serious extrapyramidal side effects such as tardivedyskinesia. Doses which are too low can provide ineffective treatmentof, e.g. schizophrenic symptoms, which can be disastrous to a patient'squality of life, while doses which are too high can cause serious andsometimes irreversible side effects. Because the plasma levels ofaripiprazole can be significantly affected by the rate at which the drugis metabolized in the patient, it is important to account for the CYP2D6and CYP3A4 isozyme function of a patient in order to achieve thedesired, clinically effective plasma levels of aripiprazole, whileminimizing side effects.

Many drugs are metabolized in the liver by one or more of the cytochromeP450 (CYP) family of enzymes. Aripiprazole is primarily metabolized bythe CYP2D6 and CYP3A4 isozymes. These isozymes often exhibit significantphenotypic variability, which can significantly affect the functioningof the enzyme. Most patients can be characterized as having “normal”CYP2D6 or CYP3A4 enzyme function, and readily (“extensively”) metabolizedrugs such as aripiprazole. However, some patients have little or noCYP2D6 or CYP3A4 enzyme function, and can be considered “poormetabolizers”—i.e., have a substantially reduced ability to metabolizearipiprazole, and therefore do not eliminate it as efficiently asextensive metabolizers. Such “poor metabolizers” may have about an about63-112% increase in aripiprazole exposure (an average of about 80%) andabout a 35% decrease in exposure to the active metabolite ofaripiprazole, compared to the extensive metabolizers.

Some drugs or foods act as inhibitors for CYP2D6 or CYP3A4 enzymes, andtherefore can inhibit or reduce the metabolism of aripiprazole ifconcomitantly administered or consumed within the time-frame thataripiprazole is administered, for example shortly before or afteradministration of aripiprazole. Such drugs or foods are referred to asCYP2D6 or CYP3A4 inhibitors. Similar to the effects observed for poormetabolizers, above, extensive metabolizers concomitantly administeredCYP2D6 inhibitors and/or CYP3A4 inhibitors also exhibit an approximately63-112% increase in aripiprazole exposure (average of about 80%) andabout a 35% decrease in exposure to the active metabolite ofaripiprazole. Concomitant administration of such inhibitors withcompositions which release aripiprazole (e.g., long-acting intramusculardepot compositions which systemically release aripiprazole) can beparticularly important when the patient is also a CYP2D6 or CYP3A4 poormetabolizer, since the metabolism of aripiprazole will be suppressed bythe poor metabolizer's innately low CYP2D6 or CYP3A4 enzyme activity, aswell as the further inhibition provided by the CYP2D6 or CYP3A4inhibitor. Poor metabolizers concomitantly administered CYP2D6 and/orCYP3A4 inhibitors exhibit a correspondingly greater increase inaripiprazole exposure up to 4 fold in aripiprazole concentrations.

Alternatively, some drugs can significantly increase the activity of theenzyme (e.g., act as “inducers” of the CYP2D6 or CYP3A4 enzyme), andthereby substantially increase the rate of aripiprazole metabolism. Evenfor patients who are CYP2D6 or CYP3A4 poor metabolizers, the increasedrate of metabolism of aripiprazole provided by concomitantlyadministered “inducers” may be such that intramuscular administration ofan aripiprazole-releasing suspension never provides a patient withclinically effective levels of aripiprazole.

Thus, a patient with normal CYP2D6 and CYP3A4 enzyme function is anextensive metabolizer of CYP2D6 and CYP3A4 who is not concomitantlyadministered either inhibitors or inducers of CYP2D6 or CYP3A4. Apatient with impaired CYP2D6 or CYP3A4 (or both) enzyme functionincludes patients who are CYP2D6 and/or CYP3A4 poor metabolizers,patients who are extensive metabolizers administered strong CYP2D6and/or CYP3A4 inhibitors, and patients who are CYP2D6 and/or CYP3A4 poormetabolizers concomitantly administered strong CYP2D6 and/or CYP3A4inhibitors.

Aripiprazole is typically administered as a conventional once-daily oraldosage form (e.g., a tablet) or a once-daily, immediate releaseinjectable solution (which is distinct from the injectable depotformulations of the present method which provide sustained systemicrelease of aripiprazole over a significant period of time, e.g. aboutone month). Aripiprazole dosing is readily adjusted in once-dailyformulations by appropriately increasing or decreasing the subsequentdaily dose. However, some schizophrenic patients may resist or evadecomplying with the recommended oral dosing regime, or otherwise havedifficulty in complying with regular dosing, which can make optimaltreatment difficult. Treatment of such patients can be improved byadministering a long-acting, injectable intramuscular depot formulation.The intramuscular depot formulation slowly releases clinically effectivelevels of aripiprazole into the bloodstream (plasma) of the patient overabout a month, and therefore avoids compliance issues related to dailydosing. In addition, because the intramuscular depot formulation isinjected, it must typically be administered by the treating physician,(rather than by the patient him/herself, as for oral dosage forms),further ensuring patient compliance.

Dosing for oral and intramuscular depot formulations differs in that thedrug from an oral formulation is released in the digestive tract andabsorbed through the hepatic portal system where the drug can bemetabolized by hepatic enzymes (e.g., CYP2D6 and CYP3A4) before it isdistributed systemically through the patient. In contrast, intramusculardepot formulations release the drug directly into the patient'sbloodstream over an extended period, thereby avoiding initial hepaticenzyme metabolism. Accordingly, the drug exposure provided by anintramuscular depot formulation would not be expected to be the same asthat of an oral formulation. Thus dose adjustments suitable for patientswith impaired CYP2D6 and/or CYP3A4 enzyme function are not the same asthose suitable for patients treated with aripiprazole releasing depotformulations.

In addition, because an intramuscular depot formulation is administeredso infrequently (e.g., monthly), dose adjustments cannot be made asreadily as for once-daily formulations, and any problems with over- orunder-dosing cannot be rectified rapidly. Accordingly, there is a riskthat administration of an inappropriate dose of a drug provided in theform of an intramuscular depot formulation would result in extendedperiods of under-dosing or over-dosing before the optimal dose wasachieved, with the consequent risks to the patient's quality of life orexposure to the risk of serious side effects. Thus, there is a need formethods of initiating treatment with aripiprazole-releasing depotformulations that provide an appropriate aripiprazole starting dose topatients, particularly patients with impaired CYP2D6 or CYP3A4 enzymefunction.

The starting dose of aripiprazole released from an intramuscularlyadministered dosage form for a patient with impaired CYP2D6 or CYP3A4enzyme function, for example a patient who is a CYP2D6 or CYP3A4 poormetabolizer, according to the present method, can be described inreference to the initial dose recommended for a patient with normalCYP2D6 and CYP3A4 enzyme function. For example, the recommended initialdose of an intramuscularly administered depot dosage form which releasesaripiprazole systemically into a patient with normal CYP2D6 or CYP3A4enzyme function is typically about 400 mg or about 300 mg (expressed asan equivalent weight of aripiprazole).

For a patient with impaired CYP2D6 or CYP3A4 enzyme function who is aCYP2D6 poor metabolizer or CYP3A4 poor metabolizer, the starting doseaccording to the present method would be about 75% of the recommendedinitial dose of 400 mg of aripiprazole for a patient with normal CYP2D6or CYP3A4 enzyme function (i.e., about 300 mg, expressed as anequivalent weight of aripiprazole). For a patient with impaired CYP2D6or CYP3A4 enzyme function who is a CYP2D6 poor metabolizer or a CYP3A4poor metabolizer, and is concomitantly administered a strong CYP2D6 orCYP3A4 inhibitor, (in particular, patients who are CYP2D6 or CYP3A4 poormetabolizers and concomitantly administered a strong CYP2D6 or CYP3A4inhibitor for about 14 days or more during treatment with a long-actingdrug-containing suspension which delivers therapeutic plasma levels ofaripiprazole) the starting dose according to the present method would beabout 50% of the recommended initial dose of 400 mg of aripiprazole fora patient with normal CYP2D6 or CYP3A4 enzyme function (i.e. about 200mg, expressed as an equivalent weight of aripiprazole).

In alternative embodiments, the patient with impaired CYP2D6 or CYP3A4enzyme function can be an extensive metabolizer (rather than a CYP2D6 orCYP3A4 poor metabolizer), who is concomitantly administered a strongCYP2D6 or CYP3A4 inhibitor, in particular, patients who are extensivemetabolizers and concomitantly administered a strong CYP2D6 or CYP3A4inhibitor for about 14 days or more during treatment with a long-actingdrug-containing suspension which delivers therapeutic plasma levels ofaripiprazole. For such patients, the starting dose can provide about 66%to about 75%, for example, about 66% of the amount of aripiprazolecompared to the initial dose recommended for a patient with normalCYP2D6 and CYP3A4 enzyme function or about 75% of the amount ofaripiprazole compared to the initial dose recommended for a patient withnormal CYP2D6 and CYP3A4 enzyme function. If the recommended initialdose for a patient with normal CYP2D6 or CYP3A4 enzyme function is 400mg of aripiprazole, the starting dose for a patient with impaired CYP2D6or CYP3A4 enzyme function who is an extensive metabolizer concomitantlyadministered a strong CYP2D6 or CYP3A4 inhibitor according to thepresent method would be about 75% of the recommended initial dose (i.e.,about 300 mg, expressed as the equivalent weight of aripiprazole). Ifthe recommended initial dose for a patient with normal CYP2D6 or CYP3A4enzyme function is 300 mg of aripiprazole, the starting dose for apatient with impaired CYP2D6 or CYP3A4 enzyme function who is anextensive metabolizer concomitantly administered a strong CYP2D6 orCYP3A4 inhibitor according to the present method would be about 66% ofthe recommended initial dose (i.e., about 200 mg, expressed as theequivalent weight of aripiprazole).

In yet other embodiments, the patient with impaired CYP2D6 or CYP3A4enzyme function can be an extensive metabolizer (rather than a CYP2D6 orCYP3A4 poor metabolizer), who is concomitantly administered both astrong CYP2D6 and a strong CYP3A4 inhibitor. If the recommended initialdose for a patient with normal CYP2D6 or CYP3A4 enzyme function is 400mg of aripiprazole, the starting dose for a patient with impaired CYP2D6or CYP3A4 enzyme function who is an extensive metabolizer concomitantlyadministered both a strong CYP2D6 and a strong CYP3A4 inhibitoraccording to the present method would be about 50% of the recommendedinitial dose (i.e., about 200 mg, expressed as the equivalent weight ofaripiprazole). If the recommended initial dose for a patient with normalCYP2D6 or CYP3A4 enzyme function is 300 mg of aripiprazole, the startingdose for a patient with impaired CYP2D6 or CYP3A4 enzyme function who isan extensive metabolizer concomitantly administered both a strong CYP2D6and a strong CYP3A4 inhibitor according to the present method would beabout 53% of the recommended initial dose (i.e., about 160 mg, expressedas the equivalent weight of aripiprazole).

In still other embodiments, a patient taking a CYP2D6 or CYP3A4 inducer,should entirely avoid intramuscularly administered dosage forms whichrelease aripiprazole.

The intramuscular administration step can involve any suitable form ofintramuscular administration, and is most commonly intramuscularinjection. The injection can be to any suitable muscle, such as thedeltoid muscle, the vastus lateralis muscle, or a gluteal muscle, forexample, the ventrogluteal or dorsogluteal muscle.

The long-acting drug-containing suspension can comprise aripiprazole ora prodrug thereof. Many aripiprazole prodrugs are known in the art andare disclosed, for example, in U.S. Pat. Pub. 2011/0003828, U.S. Pat.Pub. 2011/0015156 (now U.S. Pat. No. 8,431,576), U.S. Pat. Pub.2011/0178068, U.S. Pat. Pub. 20110151711, U.S. Pat. Pub. 2012/0202823,U.S. Pat. Pub. 2012/0238552, and U.S. Pat. Pub. 2013/0053301. Particularprodrugs include those disclosed in U.S. Pat. Pub. 2011/0015156 (nowU.S. Pat. No. 8,431,576), such as(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate, the structure of which appears on FIG. 2.

The aripiprazole or prodrug thereof can have a mean particle size ofabout 1 to about 30 microns, such as about 1 to about 20 microns, about1 to about 15 microns or about 2 to about 4 or about 2.5 microns inorder to provide or release aripiprazole systemically such that atherapeutic plasma level of aripiprazole in the subject is obtained overa period of about one month.

In addition to the aripiprazole or prodrug thereof, the long-actingdrug-containing suspension can comprise a solvent for injection and avehicle for the aripiprazole or prodrug thereof. The solvent forinjection can comprise water, for example in the form of Ringer'ssolution, isotonic sodium chloride solution, etc. In other embodiments,the solvent can comprise an oil, such as natural or synthetic mono- ordiglycerides, fatty acids, etc.

The vehicle can include one or more of at least one suspending agent, atleast one bulking agent, at least one buffer, and at least one pHadjusting agent. Exemplary vehicles are disclosed in U.S. Pat. No.8,030,313.

The at least one suspending agent, when used, can be present in anamount of from about 0.2% to about 10%, such as from about 0.5% to about5%. Exemplary suspending agents are disclosed in U.S. Pat. No.8,030,313. Particular exemplary suspending agents include carboxymethylcellulose or its sodium salt.

The at least one bulking agent, when used, can be present in an amountof from about 1% to about 10%, such as about 3% to about 8%, or about 4%to about 5%. Exemplary bulking agents are disclosed in U.S. Pat. No.8,030,313. Particular exemplary bulking agents are sorbitol and xylitol.

The at least one buffer, when used, can be used in amount required toadjust the pH of an aqueous suspension from a pH of about 6 to about 8,such as about 7, and can be incorporated into the aqueous suspension inan amount of from about 0.02% to about 2%, about 0.03% to about 1%, orabout 0.1%. Exemplary buffers are also disclosed in U.S. Pat. No.8,030,313. Particular exemplary buffers include sodium phosphate,potassium phosphate, and TRIS.

The at least one pH adjusting agent, when used, can be used in an amountrequired to adjust the pH from about 6 to about 7.5, such as about 7.The pH adjusting agent can be an acid, such as hydrochloric acid, whenthe pH must be lowered or a base, such as sodium hydroxide, when the pHmust be raised. Exemplary pH adjusting agents are also disclosed in U.S.Pat. No. 8,030,313.

In other embodiments, the long-acting drug-containing suspension cancomprise aripiprazole or a prodrug of aripiprazole, which in either casecan be microencapsulated into a matrix, such as a biodegradable polymer,for example polylactide-polyglycolide. Alternatively, the aripiprazoleor prodrug of aripiprazole can be entrapped in the liposomes or in amicro-emulsion compatible with body tissues.

The patient with impaired CYP2D6 or CYP3A4 enzyme function can be aCYP2D6 poor metabolizer, a CYP3A4 poor metabolizer, or both a CYP2D6poor metabolizer and a CYP3A4 poor metabolizer. In addition, the patientcan be schizophrenic, aripiprazole naïve, or both schizophrenic andaripiprazole naïve.

In alternative embodiments, the patient with impaired CYP2D6 or CYP3A4enzyme function can be a CYP2D6 poor metabolizer, a CYP3A4 poormetabolizer, or both a CYP2D6 poor metabolizer and a CYP3A4 poormetabolizer and concomitantly administered a strong CYP2D6 inhibitor ora strong CYP3A4 inhibitor, or both a strong CYP2D6 and a strong CYP3A4inhibitor. In still other embodiments, the patient with impaired CYP2D6or CYP3A4 enzyme function can be an extensive metabolizer (i.e., not aCYP2D6 or CYP3A4 poor metabolizer), and concomitantly administered astrong CYP2D6 inhibitor or a strong CYP3A4 inhibitor, or both a strongCYP2D6 and a strong CYP3A4 inhibitor.

In still other embodiments, the patient with impaired CYP2D6 or CYP3A4enzyme function can be administered a CYP2D6 or CYP3A4 inducer. CYP3A4inducers known in the art include carbamezepine, phenytoin,oxcarbazepine, barbiturates such phenobarbital, St. John's Wort,rifampicin, rifabutin, efavirenz, nevirapine, pioglitazone,troglitazone, glucocorticoids, modafinil, etc. CYP2D6 inducers includedexamethasone, rifampicin, glutethimide, etc. 100401 Strong CYP3A4inhibitors are known in the art, and include aminodarone, anastrozole,azithromycin, cannabinoids, cimetidine, clarithromycin, clotrimazole,cyclosorine, danazol, delavirdine, dexamethasone,diethyldithiocarbamate, diltiazem, dirithryromycin, disulfiram, ethinylestradiol, fluconazole, fluoxetine, fluoaxamine, gestodene, grapefruitjuice, indinavir, isoniazid, ketoconazole, metronidazole, mibefradil,miconazole, nefazodone, nelfinavir, nevirapine, norfloxacin,norfluoxetine, omeprazole, oxiconazole, propoxyphene, quinine,quinupristine, ranitidine, ritonavir, saquinavir, sertindole,sertraline, troglitazone, troleandomycin, valproic acid, etc. ModerateCYP3A4 inhibitors include erythromycin and grapefruit juice.

Strong CYP2D6 inhibitors are also known in the art, and includeamiodarone, celecoxib, choroquine, chlorpromazine, cimetidine,citalopram, codeine, deiavirdine, desipramine, dextropropoxyphene,diltiazam, doxorubicin, fluoxetine, fluphenazine, fluvoxamine,haloperidol, labetalol, lobeline, lomustine, methadone, mibefradil,moclobemide, nortuloxeline, paroxetine, propafenone, quinacrine,quinidine, ranitidine, ritonavir, serindole, thioridazine, valproicacid, vinblastine, vincristine, vinorelbine, yohimbine, etc.

The patient with impaired CYP2D6 and/or CYP3A4 enzyme function can becoadministered an oral antipsychotic after administration of thestarting dose of the long-acting drug-containing suspension whichprovides aripiprazole systemically, for example for at least the first14 days after administration of the starting dose. The oralantipsychotic can comprise aripiprazole, such as about 10 mg per day orabout 20 mg per day of aripiprazole. As discussed above, a steady statelevel of aripiprazole may not be reached until several weeks or monthsafter the starting dose of the long-acting drug-containing suspensionwhich which provides aripiprazole systemically is administered. Thus,coadministration of an oral antipsychotic, such as oral aripiprazole,can be helpful to raise the patient's plasma levels of aripiprazoleshortly after initiating treatment.

The starting dose of the long-acting drug-containing suspension whichprovides aripiprazole systemically can contain aripiprazole or a prodrugthereof, and can provide therapeutic plasma levels of aripiprazole forabout one month. After about one month, the patient can be maintained ona monthly maintenance dose of a long-acting aripiprazole-releasingsuspension, which can be the same as or different from the long-actingaripiprazole-releasing suspension used to administer the starting dose.For example, the maintenance dose can be administered intramuscularly.The maintenance dose of a long-acting aripiprazole-releasing suspensioncan systemically release a predefined amount of aripiprazole in eachdose, for example, no more than 400 mg of aripiprazole per dose.

Example 1

A long-acting aripiprazole-releasing suspension was manufactured asfollows. A microparticulate dispersion of aripiprazole was preparedusing a DYNO®-MILL (Type KDL A, manufactured by Willy A. Bachoffen AGMaschinefabrik, Basel, Switzerland). The ingredients of Table 1 wereadded to a 3 L glass jacketed vessel maintained at 15° C. (±5° C.) toform a sterile primary suspension.

TABLE 1 Component Mass Aripiprazole 100 g  Sodium carboxymethylcellulose 7L2P 9.2 g Mannitol  45 g Sodium phosphate monobasic 0.9 gSodium hydroxide solution, 1N q.s. to adjust pH to 7.0 Water forinjection q.s. to 1040 g

The primary suspension was mixed at 500-1,000 rpm for about 0.5 hoursand then at 300-500 rpm for an additional 1 hour under a vacuum of 20″Hg (+5″ Hg).

A media mill was prepared for media milling. The grinding container waspartially filled with zirconium oxide beads and the dispersion waspassed through the mill at the following a suspension flow rate of 10L/h with a milling time of 6 minutes.

2.5 mL of the resulting milled suspension were aseptically filled intosterilized vials which were then aseptically partially stoppered withsterilized stoppers. The vials were aseptically transferred to a freezedryer and lyophilized according to the following cycle:

(a) thermal treatment: freeze product at −40° C. over 0.1-1 h andmaintain at −40° C. for at least 3 h;

(b) cool the condenser to −50° C. or below;

(c) primary drying: lower the chamber pressure to about 100 microns Hgand increase the product temperature to −5° C. over about 2 hours, thenmaintain primary drying for at least 48 hours;

(d) stopper the vials under atmospheric pressure or partial vacuum usingsterile nitrogen or air and remove from the freeze dryer; and

(e) seal the vials with appropriate seals and label them.

Example 2

A patient who is a CYP2D6 poor metabolizer is administered a startingdose of aripiprazole by intramuscularly injecting a long-actingsuspension comprising the aripiprazole prodrug(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate, a vehicle, and water into a gluteal muscle. The startingdose contains sufficient(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate to provide a therapeutic concentration of aripiprazole thatis between 66% and 75% of the recommended initial dose for a patientwith normal CYP2D6 and CYP3A4 enzyme function. After one month, amaintenance dose is delivered intramuscularly by way of intramuscularinjection of a second dose of long-acting drug-containing suspensioncomprising(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate. The maintenance dose has sufficient(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl dodecanoate to systemically deliver about 400 mg ofaripiprazole over about one month.

1. A method of initiating aripiprazole treatment in a patient in needthereof who is (a) a CYP2D6 poor metabolizer not concomitantlyadministered a strong CYP3A4 or CYP2D6 inhibitor, or (b) an extensivemetabolizer concomitantly administered a strong CYP2D6 or CYP3A4inhibitor, comprising: administering intramuscularly to said patient astarting dose of a long-acting drug-containing suspension which providestherapeutic plasma levels of aripiprazole over a period of about onemonth; wherein said starting dose provides about 75% of the amount ofaripiprazole compared to an initial dose recommended for a patient withnormal CYP2D6 and CYP3A4 enzyme function. 2-3. (canceled)
 4. A method ofinitiating aripiprazole treatment in a patient in need thereof who iseither (a) a CYP2D6 poor metabolizer and is concomitantly administered astrong CYP3A4 inhibitor, or (b) an extensive metabolizer concomitantlyadministered a strong CYP3A4 and a strong CYP2D6 inhibitor, said methodcomprising: administering intramuscularly to said patient a startingdose of a long-acting drug-containing suspension which providestherapeutic plasma levels of aripiprazole over a period of about onemonth, wherein said starting dose provides about 50% of the amount ofaripiprazole compared to the initial dose recommended for a patient withnormal CYP2D6 and CYP3A4 enzyme function. 5-11. (canceled)
 12. Themethod of claim 1, wherein said patient is schizophrenic.
 13. The methodof claim 1, wherein said patient is aripiprazole naïve.
 14. (canceled)15. The method of claim 1, wherein said starting dose systemicallyreleases about 300 mg of aripiprazole.
 16. The method of claim 4,wherein said starting dose systemically releases about 200 mg ofaripiprazole. 17-18. (canceled)
 19. The method of claim 1, wherein saidlong-acting drug-containing suspension comprises aripiprazole or aprodrug thereof.
 20. The method of claim 19, wherein said long-actingdrug-containing suspension comprises(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate.
 21. The method of claim 19, wherein said long-actingdrug-containing suspension comprises a prodrug of aripiprazole.
 22. Themethod of claim 4, wherein said patient is schizophrenic.
 23. The methodof claim 4, wherein said long-acting drug-containing suspensioncomprises aripiprazole or a prodrug thereof.
 24. The method of claim 23,wherein said long-acting drug-containing suspension comprises a prodrugof aripiprazole.
 25. The method of claim 23, wherein said long-actingdrug-containing suspension comprises(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate.
 26. The method of claim 4, wherein said patient isaripiprazole naïve.
 27. The method of claim 15, wherein said patient isa CYP2D6 poor metabolizer not concomitantly administered a strong CYP3A4or CYP2D6 inhibitor.
 28. The method of claim 15, wherein said patient isan extensive metabolizer concomitantly administered a strong CYP2D6 orCYP3A4 inhibitor.
 29. The method of claim 16, wherein said patient is aCYP2D6 poor metabolizer and is concomitantly administered a strongCYP3A4 inhibitor.
 30. The method of claim 16, wherein said patient is anextensive metabolizer concomitantly administered a strong CYP3A4 and astrong CYP2D6 inhibitor.